TY - JOUR
T1 - Fimepinostat (CUDC-907) in patients with relapsed/refractory diffuse large B cell and high-grade B-cell lymphoma
T2 - report of a phase 2 trial and exploratory biomarker analyses
AU - Landsburg, Daniel J.
AU - Barta, Stefan K.
AU - Ramchandren, Radhakrishnan
AU - Batlevi, Connie
AU - Iyer, Swaminathan
AU - Kelly, Kevin
AU - Micallef, Ivana N.
AU - Smith, Sonali M.
AU - Stevens, Don A.
AU - Alvarez, Mariano
AU - Califano, Andrea
AU - Shen, Yao
AU - Bosker, Gideon
AU - Parker, Jefferson
AU - Soikes, Raul
AU - Martinez, Elizabeth
AU - von Roemeling, Reinhard
AU - Martell, Robert E.
AU - Oki, Yasuhiro
N1 - Publisher Copyright:
© 2021 British Society for Haematology and John Wiley & Sons Ltd
PY - 2021/10
Y1 - 2021/10
N2 - Fimepinostat (CUDC-907), a first-in-class oral small-molecule inhibitor of histone deacetylase and phosphatidylinositol 3-kinase, demonstrated efficacy in a phase 1 study of patients with relapsed/refractory (R/R) diffuse large and high-grade B-cell lymphomas (DLBCL/HGBL), particularly those with increased MYC protein expression and/or MYC gene rearrangement/copy number gain (MYC-altered disease). Therefore, a phase 2 study of fimepinostat was conducted in this patient population with 66 eligible patients treated. The primary end-point of overall response (OR) rate for patients with MYC-IHC ≥40% (n = 46) was 15%. Subsequently, exploratory pooled analyses were performed including patients treated on both the phase 1 and 2 studies based upon the presence of MYC-altered disease as well as a biomarker identified by Virtual Inference of Protein activity by Enriched Regulon analysis (VIPER). For these patients with MYC-altered disease (n = 63), the overall response (OR) rate was 22% with seven responding patients remaining on treatment for approximately two years or longer, and VIPER yielded a three-protein biomarker classification with positive and negative predictive values of ≥85%. Prolonged durations of response were achieved by patients with MYC-altered R/R DLBCL/HGBL treated with single-agent fimepinostat. Combination therapies and/or biomarker-based patient selection strategies may lead to higher response rates in future clinical trials.
AB - Fimepinostat (CUDC-907), a first-in-class oral small-molecule inhibitor of histone deacetylase and phosphatidylinositol 3-kinase, demonstrated efficacy in a phase 1 study of patients with relapsed/refractory (R/R) diffuse large and high-grade B-cell lymphomas (DLBCL/HGBL), particularly those with increased MYC protein expression and/or MYC gene rearrangement/copy number gain (MYC-altered disease). Therefore, a phase 2 study of fimepinostat was conducted in this patient population with 66 eligible patients treated. The primary end-point of overall response (OR) rate for patients with MYC-IHC ≥40% (n = 46) was 15%. Subsequently, exploratory pooled analyses were performed including patients treated on both the phase 1 and 2 studies based upon the presence of MYC-altered disease as well as a biomarker identified by Virtual Inference of Protein activity by Enriched Regulon analysis (VIPER). For these patients with MYC-altered disease (n = 63), the overall response (OR) rate was 22% with seven responding patients remaining on treatment for approximately two years or longer, and VIPER yielded a three-protein biomarker classification with positive and negative predictive values of ≥85%. Prolonged durations of response were achieved by patients with MYC-altered R/R DLBCL/HGBL treated with single-agent fimepinostat. Combination therapies and/or biomarker-based patient selection strategies may lead to higher response rates in future clinical trials.
KW - MYC
KW - biomarker
KW - diffuse large B-cell lymphoma
KW - histone deacetylase inhibitor
KW - phosphatidylinositol 3-kinase inhibitor
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U2 - 10.1111/bjh.17730
DO - 10.1111/bjh.17730
M3 - Article
C2 - 34341990
AN - SCOPUS:85111899053
SN - 0007-1048
VL - 195
SP - 201
EP - 209
JO - British journal of haematology
JF - British journal of haematology
IS - 2
ER -